Bruton's tyrosine kinase (Btk) belongs to tyrosine kinases, a subfamily of protein kinases that phosphorylate protein on the phenolic moiety of tyrosine residue. It is a non-receptor cytoplasmic tyrosine kinase and a key regulator for B-cell development, activation, signaling and survival (Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282; Niiro and Clark, Nature Rev. Immumol. 2002, 945; Di Paolo and Currie, Nat. Chem. Biol. 2011, 7). Btk is expressed in all hematopoietic cell types, excluding plasma cells, T lymphocytes and natural killer cells. After activation by upstream B-cell antigen receptor or Toll like receptor-4, Btk induces PLC-γ2 phosphorylation, which ultimately results in activation of nuclear factor κB (NFκB) and nuclear factor of activated T cell dependent pathways. Additionally, Btk is crucial for number of other hematopoetic cell signaling; such as, Fcγ-mediated inflammatory cytokine production (such as TNF-α, IL1β and IL6) in monocytes/macrophages, IgE mediated signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells etc (Jeffries et al. J. Biol. Chem. 2003, 26258; Horwood et al., J. Experimental Med. 2003, 1603).
Use of B-cell depleting protein based therapeutics (for example, Rituxan, a CD20 antibody) for the treatment of a number of autoimmune and/or inflammatory diseases provides enough evidence for the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory disease. And as Btk is essential for B-cell activation, this also provides an indirect rational for the role of Btk in autoimmune and/or inflammatory diseases.
Additional rationales for the involvement of Btk in various autoimmune and/or inflammatory diseases come from Btk deficient mouse models; for example, Btk deficiency has been shown to result in a marked amelioration of disease progression, in murine preclinical model of systemic lupus erythematosus (SLE). BTK deficient mice are resistant to develop collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immumol. 1993, 459).
Pharmacological validation for the involvement of Btk in various autoimmune and/or inflammatory diseases comes from two different class of Btk inhibitors, for example, (a) an irreversible Btk inhibitor (Pan et al, Chem. Med. Chem. 2007, 58), and (b) a reversible Btk inhibitor (Di Paolo, Nat. Chem. Biol. 2010, 41). Both the type of inhibitors have demonstrated efficacy in a mouse model of arthritis. PCI-32765 (an irreversible Btk inhibitor), has shown promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Burger et al, Blood 2010, 32 & J Clin Oncol 2011, 6508). Thus, small molecule Btk inhibitors are expected to be useful to treat disease processes that involve B-cell activation.
Several prior art literature describe the discovery of small molecule Btk inhibitors (for a recent review, Lou et al. J. Med. Chem. 2012). As for example, amino-pyrazolo-pyrimidine (WO2011046964A2) and imidazo[1,5-a]quinoxalines (Kim et al, Bio-org. Med. Chem. Lett., 2011, 6258) based compounds, which utilize its acrylamide functionality for covalent modification of the target protein, are published as irreversible inhibitors. There are literature prior art disclosing reversible Btk inhibitors, such as, substituted amino-pyrimidine analogs (WO2010123870A1); imidazo[1,2-f][1,2,4]triazine core based amide compounds (WO2010068810A2); various heterocyclic (e.g. imidazo[1,2-a]pyrazine, aminopyrimidine, 2-pyridone etc) amide derivatives (WO2010068788A1, WO2010068806A1); benzo[f][1,4]oxazepin analogs (WO2010122038A1); 3,4-dihydro-2H-isoquinoline or 2H-isoquinolin-1-one based analogs (WO2010100070A1, WO2013024078); phenylimidazopyrazine analogs (WO2010006970A1); 3,5-disubstituted pyrid-2-one analogs (WO2007027729A1); azaindazole compounds (WO2011019780A1); nicotinamide compounds (WO2010144647A1); carbazole carboxamide analogs (WO2010080481A1), pyrrolopyrimidine derivatives (WO2013008095).
Despite several discoveries in this area, there is no small molecule Btk inhibitor available in the market. The most advanced compounds in the clinical trials are irreversible inhibitors of Btk. Such an irreversible mechanism of action often encounters nonspecific binding with proteins including off-targets leading to safety concern particularly upon long term used such as off-target related adverse side effects, general hepatotoxicity and organ toxicity, antibody mediated reactions. Therefore, there is a need of Btk inhibitors with safer mechanism of action such as reversible mechanism of inhibition. These compounds will have medical application in the disease area of inflammation, autoimmune disorder and cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases and asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus erythematosus.